Genetic damage that increases activity of the ras pathway of man is frequently associated with oncogenic transformations. Compounds that inhibit the action of activated ras pathway might be used as anticancer agents. Another well-studied ras pathway controls cell determination in development of the hermaphrodite vulva of the nematode Caenorhabditis elegans. Recent analyses show that the components of the C. elegans ras pathway are close homologues of those of the mammalian ras pathway that controls mitogenesis. Furthermore several compounds, which can block ras- induced transformation of mammalian cells, appear to suppress the activated ras pathway of C. elegans. The aim of this project is to develop and test C. elegans-based screens for compounds that decrease activity of the C. elegans ras pathway. During Phase I, we will develop a primary high-throughput screen and test its sensitivity to compounds known to be active on the mammalian ras pathway. In addition, we will investigate secondary screens for establishing the site of drug action within the ras pathway. During Phase II we will expand the capabilities of secondary screens and apply the technologies in partnership with major pharmaceutical companies.